onists. Both appear to inhibit growth by significantly decreasing the proportion of cells in the S-phase of the cell cycle; cells accumulate in G0/G1 possibly due to increase in the G1 transit time (Sutherland et al., 1988; Michna et al, 1990).
Although the majority of studies using cell culture models ascribe growth-inhibitory properties to progestins and to antiprogestins through direct effects involving PRs, contradictory results have also been reported. Given the fact that at physiological levels, progesterone is believed to be mitogenic in the normal breast (see above), it is not entirely surprising that Moore and colleagues (Hissom and Moore, 1987) consistently report proliferative effects of R 5020 at all doses in T47D cells. It is surprising, however, that RU 486 also stimulates growth in these cells (Bowden et al., 1989). The explanation for this discrepancy is unknown. However, it is now clear that T47D cells are exceptionally unstable; during prolonged time in culture, subpopulations can develop that are phenotypically different from the parental stocks, and some of these subpopulations may have responses to hormones that differ outright from the expected response. For example, some sublines or subpopulations of T47D cells respond to high doses of tamoxifen by growth stimulation (Graham et al., 1990, 1992). In the case of tamoxifen, these aberrant responses may be mediated by the presence of mutant or variant ER (Graham et al., 1990). By analogy, it is possible that the T47D cells of Moore and his colleagues have arisen from a subpopulation harboring a mutant PR. This scenario would be very interesting, but the PRs of these cells have not been analyzed in detail. Less interesting trivial explanations for discrepancies among laboratories studying growth regulation by progestins in cell culture are discussed above (see also Clark and Sutherland, 1990).
The antiproliferative properties of progesterone antagonists are well documented in animal models of hormone-dependent mammary cancer. These include rats bearing DMBA-induced or nitroso-methyl urea (NMU)-induced tumors, and mice bearing the transplantable MXT tumor line. Growth of these tumors is inhibited by ovariectomy and maintained by physiological doses of estrogens (Bakker et al., 1989, 1990; Klijn et al., 1989; Michna et al., 1989a, b; Schneider et al., 1989). While treatment of rats with progestins at the time of DMBA administration accelerates tumor formation (Huggins and Yang, 1962; Huggins, 1965; Welsch, 1985), prophylactic treatment of rats with RU 486 at the time of DMBA administration delays the initial appearance of tumors from an average of 39 days to 81 days (Bakker et al., 1987). The reversal by progesterone of the inhibition of tumor induction produced by